PROJECT SUMMARY Molecular oxygen is very close to the ideal oxidant: it is inexpensive, abundant, has minimal toxicity, and is environmentally benign (i.e. ?green?). Since most substrates are kinetically inert to O2, oxidations with O2 must be catalyzed, most often by transition-metals. However, O2 is seldom used in the production of active pharmaceutical ingredients, in part because its reactions are thought to be hard to control, leading to overoxidation or diminished selectivity. This is a direct contradiction with the abundance of mild and selective aerobic oxidations catalyzed by Nature; many such oxidations use a transition-metal in the active site. The goal of this proposal is to gain a better understanding of the reactions of O2 and various transition-metal fragments. Palladium-catalyzed reactions are particularly promising for further development. Such catalysts have already been used in aerobic oxidation reactions, but are relatively inefficient when compared to traditional Pd- catalyzed transformations, such as cross-coupling. The problem lies in the reoxidation steps; if reoxidation with O2 were more efficient, then the catalyst would be more robust! Surprisingly little is known about what factors result in clean and fast reoxidation reactions. These factors will be elucidated by carrying out a detailed mechanistic study: isolating and synthesizing reactive Pd0 sources, then subjecting them to (and monitoring the reactions with) O2. The resulting PdII-peroxo species can be converted to useful, on-cycle intermediates by a protonation reaction, and so careful mechanistic studies will be carried out on the protonation as well. A series of these studies will provide comprehensive guidelines into ligand and substrate selection for all aerobic palladium-catalyzed reactions, leading to an accelerated timeline for future reaction development, especially towards the production of active pharmaceutical ingredients.